1. Field of the Invention
Embodiments of the present invention relate generally to the field of microparticles for the controlled delivery of pharmacologically active agents over a prolonged period of time. In particular, embodiments of the present invention are directed to microparticles having one or more layers or coatings that are capable of delivering one or more pharmacologically active agents either simultaneously or in series over a prolonged period of time, at the same or different release rates. Embodiments of the present invention are further directed to methods for the production of microparticles having a high concentration of active ingredient and a low residual solvent concentration.
2. Description of Related Art
Microparticles, suitable for the controlled release of an active ingredient, such as various drugs, and a process for preparing and using said microparticles, have been described for example, in U.S. Pat. No. 4,568,559, U.S. Pat. No. 4,623,588, and U.S. Pat. No. 5,648,097, all of which are hereby incorporated by reference in their entireties. As disclosed, microparticles are typically comprised of solid composite core material of a uniform dispersion of finely divided active ingredients or solid solution of a drug in a core-forming polymer and include a generally outer wall coating about the composite core material, to provide for the desired controlled or sustained release of the active ingredient from the microparticles. Further, the active ingredient may comprise a dissolved or finely divided, active, drug-type ingredient for the treatment of a mammal and generally the core forming polymers would be comprised of a biodegradable polymer with the outer uniform wall thickness also including a biodegradable polymer, with a size of typically less than about 200 microns to provide for an injectable form for the microparticles.
The particles are typically prepared with varying organic solutions of the active ingredient and the core-forming polymer such as, for example, employing methylene chloride to aid in the solution of the active ingredient and then removing the solvent to provide a dry composite admixture of the active ingredients and the core-forming polymer material. The dry composite admixture so prepared is then pulverized or ground-up and then screened to provide composite core particles of a defined particle size. The ground-up, reduced, and selected drug polymer admixture may then be coated with a film-forming polymer material to form a microcapsule having a generally uniform outer wall coating about the ground-up composite core material used.
In other methods of making microparticles having a core of active ingredient material, a polymer material is dispersed in a solvent and blended with a solution containing an active ingredient to be encapsulated by the polymer. As solvent is withdrawn from the dispersion, e.g., by evaporation or extraction, microparticles of the polymer material form and encapsulate a solution of core active ingredient. See U.S. Pat. Nos. 3,523,906 and 3,737,337. U.S. Pat. No. 3,691,090 describes a process in which a dispersion of a core material in organic solvent is added dropwise to an aqueous buffer, followed by evaporation of the organic solvent to yield microparticles containing a core material. U.S. Pat. No. 3,891,570 describes a process for preparing microspheres or microcapsules in which a solvent is used to dissolve or disperse the polymeric material and is removed by evaporation. U.S. Pat. Nos. 4,389,330 and 4,530,840 describe processes of microencapsulating an active ingredient in which solvent used to dissolve or disperse polymer material is removed in a two-step process involving low pressure evaporation of a portion of the solvent followed by an extraction of the remaining solvent.
Another method of preparing microparticles containing an active ingredient is to use a coacervating agent, such as silicone oil, which promotes polymer material to deposit as droplets of solvent swollen polymer on water droplets containing the active ingredient to be encapsulated. See U.S. Pat. Nos. 4,675,189 and 4,897,268. Other methods of preparing microparticles and microcapsules are disclosed in U.S. Pat. No. 4,542,025 and U.S. Pat. No. 5,407,609.
Conventional methods of microencapsulation use a surfactant at a concentration of greater than 0.1% to stabilize the emulsion formed when the polymer solution (usually dissolved in a solvent such as methylene chloride, ethyl acetate, methyl ethyl ketone, dimethyl sulfoxide or other suitable organic solvent) is combined with an aqueous solution of an active ingredient to be microencapsulated. Furthermore, conventional microparticles of many drugs having active ingredient concentrations, i.e., on the order of 40% to 50% w/v, release their active ingredient content very rapidly and therefore cannot be used for long sustained delivery of the drug since a large portion of the drug is composed of active ingredient. As a result, their duration of activity is short. This occurs especially with drugs that require a high dose for therapeutic efficacy. In order to deliver a sustained dose from these drugs over a maximum period of time, it is essential that the microparticles have a high drug content. Another problem with conventional microparticles is that control of the rate of release of the drug from the microparticles is limited to varying the intrinsic properties of the microparticles such as the size of the microparticles, their drug content or the type of polymer used. The intrinsic methods for controlling the release of the drug are dependent on the properties of the microparticles themselves, and are not always available to the formulator because of limitations in the daily dose of the drug, the physical-chemical properties of the drug, desirable duration of activity, and rate of degradation of the polymer.
Therefore, there is a need to develop methods for controlling the rate of release of the drug that are independent of intrinsic methods. There is also a need to develop microparticles having a high drug content that control the rate of release of the drug into surrounding media. Microparticles prepared by conventional methods are generally more easily damaged by physical force since the majority of the microparticle is comprised of active ingredient and not the polymer which forms the matrix which holds the microparticle together. As a result, microparticles having high drug concentrations and uniform structure from microparticle to microparticle are generally difficult to prepare.
Also, many conventional microcapsules share a common limiting feature in that they are designed to deliver a single active ingredient at a single release rate since existing methods of making microcapsules generally comprise forming a single polymer wall around a core containing a single active ingredient. Therefore, a need exists to develop microcapsules which are capable of delivering one or more active ingredients at the same or different release rates over a prolonged period of time. A further need exists to provide a drug delivery device in the form of a multilayered microcapsule which can be readily and simply designed to provide a specific desired release profile of one or more active ingredients tailored to optimize treatment of a particular disease or condition within a mammal, such as a human. A further need exists to develop therapeutic methods based upon the multilayered microcapsules of the present invention for treating one or more disorders with a single microcapsule design. A still further need exists to develop therapeutic methods based upon the multilayered microcapsules of the present invention for treating a single disorder with a combination of active ingredients, which is commonly referred to as a “cocktail therapy”.
An even still further need exists to provide for new and effective microcapsules which avoid at least some of the disadvantages of the prior art microcapsules, and which provide additional advantages of greater uniformity, size and ease in preparation and lower toxic solvent content than the prior art microcapsules.